CN109276537A - A kind of composite hydrogel and its preparation and application of load vascular disrupting agents and near infrared light thermal response nanoparticle altogether - Google Patents
A kind of composite hydrogel and its preparation and application of load vascular disrupting agents and near infrared light thermal response nanoparticle altogether Download PDFInfo
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Abstract
The present invention relates to a kind of injectable composite hydrogels and antitumor application thereof for loading vascular disrupting agents and near infrared light thermal response nanoparticle altogether.Composite hydrogel includes hydrogel substrate material, and the vascular disrupting agents and near infrared light thermal response nanoparticle that are supported in hydrogel substrate material.Nanometer composite hydrogel produced by the present invention has the sol-gel transition behavior of syringeability and heat stagnation.Under the irradiation of near infrared light, hybridized hydrogel of the invention has very excellent photo-thermal property, and the curative effect of vascular disrupting agents is improved by enhancing tumor vessel permeability.Good safety and curative effect are showed in anti-tumor aspect using vascular disrupting agents and the hybridized hydrogel of photo-thermal combination therapy.
Description
Technical field
The present invention relates to a kind of injection aquagels for loading vascular disrupting agents and near infrared light thermal response nanoparticle altogether
And antitumor application thereof, belong to pharmacy, oncology.
Background technique
Tumor tissues are made of essence and interstitial two parts, and tumor epithelial cell is tumour cell, are the main components of tumour, tool
Organized source specificity.The interstitial of tumour plays support and nutrition tumor epithelial cell, does not have specificity, including connective group
It knits, blood vessel, lymphatic vessel etc..
Vascular disrupting agents (vascular disrupting agents, abbreviation VDAs) are a kind of swollen with selective injury
The anti-tumor drug of tumor relevant blood vessel.This kind of drug blocks the battalion of tumor tissues by selectively destroying tumor-associated vessels
Substance and oxygen supply are supported, secondary tumors cell death is caused, to achieve the purpose that targeting therapy on tumor.However, due to
The poorly water-soluble of vasoinhibitor (such as health cloth sting A4 etc.), the originals such as half-life short, bioavilability is very low, permeability is insufficient
Cause, single vascular disrupting agents treatment frequently result in failure and the tumor recurrence of oncotherapy.
Near infrared light heat cure is the antitumor physical method of one kind of latest developments, is had using near infrared light (NIR)
The advantages that wavelength is longer, penetrability is strong, not only can be with right place rapidly local ablation tumor tissues, can also be according to infrared
The intensity of line transmitting and the related progress infrared thermal imaging of the temperature of object, photoacoustic imaging etc..Commonly optical-thermal conversion material includes
C-based nanomaterial (such as graphene etc.), nano semiconductor material (such as copper sulfide, bismuth selenide etc.), noble metal nano particles
(such as gold, platinum etc.).Prussian blue is Fe2+And Fe3+Six ferricyanides of mixed valence, preparation method is simple, mild condition,
It clinically can be used for treating thallium radiation poisoning, there is good biological safety and metabolic pathway in human body.Research hair
Existing prussian blue nano particle has the function of near infrared light fuel factor and magnetic resonance imaging enhancing.Single photo-thermal therapy is anti-swollen
It is general only to small size tumour (< 100mm when tumor3) effectively, and it is bad to be easy to cause thermal burn, pain over the course for the treatment of etc.
Phenomenon.
Currently, the hydrogel near infrared light response of research report is mainly your gold that one kind includes photo-thermal property
Hydrogel { the Biomaterials 2016,104,129-137 of metal nano-particle (such as nano platinum particle, gold nanoparticle)；
Adv.Funct.Mater.2018,28 (21), 1801000 }, and concentrate on the combination therapy of both photo-thermal and chemotherapy.Many institute's weeks
Know, side effects of chemotherapy is big, is easy to produce drug resistance.There is not yet hydrogel carrier is total to load vascular disrupting agents and near-infrared photo-thermal
Response nano particle is to realize the document report of photo-thermal and vascular disrupting agents combination therapy.
Summary of the invention
An object of the present invention is to provide a kind of load vascular disrupting agents and near infrared light thermal response nanoparticle altogether
Composite hydrogel.
Second purpose of the invention is, provides the preparation method of composite hydrogel described in one kind.
Third purpose of the present invention is, provides composite hydrogel application in preparation of anti-tumor drugs described in one kind.
A kind of composite hydrogel loading vascular disrupting agents and near infrared light thermal response nanoparticle altogether, including water-setting matrix
Bottom material, the vascular disrupting agents being supported in hydrogel substrate material and near infrared light thermal response nanoparticle.
Composite hydrogel of the invention be based on hydrogel substrate material comprising near infrared light thermal response nanoparticle and
The Nanometer composite hydrogel of vascular disrupting agents.The present invention innovatively has found, by vascular disrupting agents and near infrared light thermal response nanometer
Particle loads on the hydrogel, has obvious synergistic purpose, can promote mutual anti-tumor activity, hence it is evident that improves anti-swollen
Tumor effect, moreover, the present inventors have additionally discovered that, vascular disrupting agents and near infrared light thermal response nanoparticle are supported on together
On hydrogel, the purpose of long-acting can be realized by sustained release to avoid the burst release of vascular disrupting agents.Antitumor reality in Mice Body
Test the result shows that, compared to VDAs/ hydrogel and PB/ hydrogel is used alone, the experimental group tool that uses composite hydrogel to handle
There is better antitumous effect, it almost can complete tumor resection.
Near infrared light thermal response nanoparticle of the present invention needs to turn with good biocompatibility, higher photo-thermal
Change the material of efficiency and preferable photo and thermal stability.
Preferably, the near infrared light thermal response nanoparticle is mesoporous prussian blue nano particle ((Prussian
Blue, abbreviation PB), at least one of platinum and metal chalcogenide compound.
Further preferably, the near infrared light thermal response nanoparticle is mesoporous prussian blue nano particle.
The study found that the synergy of preferred PB and vascular disrupting agents and hydrogel substrate material is more excellent, association can be further promoted
Same effect.
Further preferably, the partial size of the near infrared light thermal response nanoparticle is 20~200nm.
Still more preferably, the near infrared light thermal response nanoparticle is particle diameter distribution in 20~200nm range, most
Mesoporous prussian blue nano particle of the big absorbing wavelength in 720nm or so.
Prussian blue nano particle described in hydrogel of the invention by polyvinylpyrrolidone (PVP) restore dispersion method,
Sodium citrate modifies the preparation of the methods of the precipitation method, hydro-thermal etching method.
Preferably, the vascular disrupting agents are health cloth sting A4 (CA4), health cloth sting A4 water-soluble phosphate precursor medicine
At least one of object CA4P, DMXAA and TZT-1027；Preferably CA4.The present inventor is the study found that preferred CA4 and described
The composite hydrogel of near infrared light thermal response nanoparticle there is more preferably synergy, can further be promoted it is antitumor and
Slow release effect.
Hydrogel matrix material of the present invention is a kind of natural polysaccharide with highest critical solution temperature (UCST), and
Sol-gel transition behavior with heat stagnation can cooperate with the other compositions in composite hydrogel, make in composite hydrogel
The fuel factor generated under nanoparticle illumination, prevents the burst release of vascular disrupting agents, and keeps vascular disrupting agents in tumor locus
Relatively high local concentration and therapeutic effect.
Preferably, hydrogel substrate material is temperature-sensitive hydrogel；Preferably, the hydrogel substrate material has
Syringeability.
Hydrogel substrate material is more preferably at least one of gellan gum, agar.Preferred base material, it is more sharp
In the performance for promoting composite hydrogel, the situ treatment ability and biocompatibility of material are further promoted.
Still more preferably, hydrogel substrate material is gellan gum；Most preferably low-acyl gellan gum.
The research of the invention finds that it is good that the composite hydrogel can be assigned under the component collaboration of the innovation
Antitumous effect, research it has furthermore been found that control component between proportionate relationship, can further promote the synergisticing performance.
Preferably, hydrogel substrate material mass percent concentration is 0.5%~5%, closely in the composite hydrogel
The mass concentration of infrared photothermal response nanoparticle is 0.01~1.0mg/mL, and vascular disrupting agents concentration is in 1.0~10.0mg/
mL。
Further preferably, in the composite hydrogel, hydrogel substrate material is gellan gum, near infrared light thermal response nanometer
Particle is the PB, vascular disrupting agents CA4 of 20~200nm；Wherein, gellan gum mass percent concentration is 0.5%~5%, PB
Mass concentration is 0.05~1mg/mL, and vascular disrupting agents concentration is in 1~10mg/mL.
The invention discloses a kind of preparation methods of composite hydrogel, by vascular disrupting agents, near infrared light thermal response
Nanoparticle and the mixing of hydrogel matrix material and water, are made the composite hydrogel.
Preparation method of the present invention exists vascular disrupting agents, near infrared light thermal response nanoparticle and host material
The composite hydrogel is made in gelation in water.
Preferably, hydrogel matrix material is added in the dispersion liquid for being dispersed near infrared light thermal response nanoparticle and adds
After heat of solution, it is cooled to the temperature range addition vascular disrupting agents drug that not will lead to drug inactivation, is cooled to room temperature, i.e.,
?.
Still more preferably, it the preparation method: after gellan gum is dissolved by heating with water, is cooled to and not will lead to drug
PB, vascular disrupting agents drug is added in the temperature range of inactivation, then cooling mixed aqueous solution can be obtained to room temperature comprising PB nanometers
The gellan gum Nanometer composite hydrogel system of particle and vascular disrupting agents.
Composite hydrogel of the present invention has the characteristics that preparation method is simple, treatment is easy to operate.Selected three
Kind material mixing can be obtained by Nanometer composite hydrogel.When treatment, it is only necessary to intratumor injection and primary or close for several times
Infrared light shines can cure tumour completely.
The present invention also provides the applications of the composite hydrogel, are used to prepare anti-tumor drug；
Preferably, it is used to prepare the drug of neoplasm in situ treatment；
Further preferably, it is used to prepare the drug of anti-malignant sarcomas.
Most preferably, the application, which is characterized in that be used to prepare antitumor ejection preparation.
The present invention also provides a kind of antitumor ejection preparations, and it includes the composite hydrogels.
Beneficial effect
Composite hydrogel of the present invention has efficient antitumor action by the collaboration of component.Work as near infrared light
When irradiation, Nanometer composite hydrogel generates fuel factor, can not only enhance tumor infiltrating, can also weaken hydrogel substrate material
Interaction between (such as gellan gum) molecule, to enhance gel network mobility, vascular disrupting agents are gradually spread therewith
To the neighboring area of injection site, tumor vascular comprehensive collapsing and tumor cell necrosis can be caused.Due to gellan gum water-setting
The heating stagnation curve of glue, gel will not be destroyed all in temperature-rise period, and the substance coated can be retained in tumor tissues
Near, preferably extend drug treating time, achievees the purpose that administration in situ, long-acting.
In addition, the present invention can solve vascular disrupting agents poorly water-soluble, half-life period by the collaboration between component well
The short, technical problems such as bioavilability is very low, permeability is insufficient；Moreover, moreover it is possible to pass through the near infrared light thermal response
Nanoparticle cooperates the hydrogel substrate material, regulates and controls the release and tissue permeability of effective component, reaches and significantly mention
Rise the purpose of antitumous effect.
Nanometer composite hydrogel of the invention simple combination absolutely not, by the collaboration of each component, described is compound
There is hydrogel the sol-gel transition behavior of heat stagnation, the fuel factor generated under light illumination not will cause vascular disrupting agents
Burst release can make vascular disrupting agents keep relatively high local concentration and therapeutic effect in tumor locus；Moreover, institute of the present invention
The composite hydrogel stated has syringeability and improves tumor vessel permeability, it can be achieved that efficient therapeutic purposes in situ, effectively
It ensure that the composite hydrogel in the good safety of anti-tumor aspect and curative effect.
Detailed description of the invention
The rheological equationm of state of 4 Nanometer composite hydrogel of Fig. 1 embodiment in heating and temperature-fall period
The shear shinning property of 4 Nanometer composite hydrogel of Fig. 2 embodiment
The strain sweep curve of 4 Nanometer composite hydrogel of Fig. 3 embodiment
The Cyclic Strain scanning curve of 3 Nanometer composite hydrogels of Fig. 4 embodiment 4
The absorption spectrum of 4 Nanometer composite hydrogel of Fig. 5 embodiment
The photo-thermal property figure of 4 Nanometer composite hydrogel of Fig. 6 embodiment
The light-operated release profiles of 6 Nanometer composite hydrogel of Fig. 7 embodiment
The antitumous effect figure of 7 Nanometer composite hydrogel of Fig. 8 embodiment
The antitumor quantization figure of 7 Nanometer composite hydrogel of Fig. 9 embodiment
Specific embodiment
Following embodiment is intended to illustrate invention rather than limitation of the invention further.
Embodiment 1.
Polyvinylpyrrolidone (PVP) restores dispersion method and prepares prussian blue nano particle
Weigh 15g polyvinylpyrrolidone (PVP) and 664mg potassium ferricyanide (K3[Fe(CN)6]), 200mL 0.01M is added
30min is stirred at room temperature in HCl, is transferred in 80 DEG C of thermostatical oil baths and reacts 20h, is cooled to room temperature after reaction, high speed centrifugation
20min removes supernatant, with secondary water washing to neutrality, is lyophilized spare.
2. sodium citrate of embodiment modifies the precipitation method and prepares prussian blue nano particle
It weighs 0.10g sodium citrate and 20mL FeCl is added3In (1mM) solution, weighs 0.10g sodium citrate and 20mL is added
K4[Fe(CN)6] in (1mM) aqueous solution, under 60 DEG C of constant temperature stirrings, by sodium citrate/K4[Fe(CN)6] mixed solution is added dropwise
In sodium citrate/FeCl3 mixed solution, after it is cooled to room temperature, continuing stirring 30min can be obtained prussian blue nano grain
Son.
The preparation of the mesoporous prussian blue nano particle of embodiment 3.
Prussian blue (Prussian blue, the PB) nanoparticle of 0.08g and 125mg PVP are weighed, 80mL is added to
In 1.0M HCl, 30min is stirred, is transferred in 100mL reaction kettle, is placed in 140 DEG C of baking ovens and reacts 4h, high speed centrifugation 20min is received
Collection precipitating is lyophilized spare with secondary water washing to neutrality.
Embodiment 4. loads the Nanometer composite hydrogel of prussian blue nano particle and CA4 altogether
It weighs 0.2g gellan gum (acyl group low with Guang Chun industry Industrial Co., Ltd) and 10mL 0.1mg/mL PB (example 3) is added
In ultrasonic disperse liquid, after mixing, it is placed in 85 DEG C of thermostat water baths, after completely dissolution to gellan gum, mixed solution is placed in 50
Place 1h in DEG C thermostat water bath, add 60mg CA4, after being sufficiently mixed uniformly, be cooled to room temperature can be obtained cladding PB with
The Nanometer composite hydrogel of CA4, sample are placed in 4 DEG C of refrigerators and are kept in dark place that (Product Labeling is CA4+PB@gellan
hydrogel)。
Embodiment 5. loads the Nanometer composite hydrogel of prussian blue nano particle and CA4P altogether
It weighs 0.2g gellan gum to be added in 10mL 0.1mg/mL PB ultrasonic disperse liquid (example 3), after mixing, is placed in 85 DEG C
In thermostat water bath, after completely dissolution to gellan gum, mixed solution is placed in 50 DEG C of thermostat water baths and places 1h, is added
30mg CA4P after being sufficiently mixed uniformly, is cooled to the Nanometer composite hydrogel that cladding PB and CA4P can be obtained in room temperature, and sample is set
(Product Labeling is CA4P+PB@gellan hydrogel) is kept in dark place in 4 DEG C of refrigerators.
The release experiment of 6. Nanometer composite hydrogel of embodiment
Two parts of 1.0g of Nanometer composite hydrogel prepared by embodiment 5 are weighed, it is slow to be separately added into 7.4 PBS of 2.0mL pH
Fliud flushing is placed in 37 DEG C of water bath with thermostatic control shaking tables as dissolution medium and simulates release.A copy of it sample applies 1.0W/cm2's
(temperature is increased to 54 DEG C) closes laser after 808nm laser irradiation 5min, so repeats four light cycles.Another is
Control group without laser irradiation.It is quantitative to the drug concentration in dissolution medium at specific time point, and draw accumulation drug and release
Put kinetic curve.
The anti-tumor experiment of 7. Nanometer composite hydrogel of embodiment
After mouse shaving, the physiological saline of 100 μ L cells containing 4T1 is subcutaneously injected, about back of mice is grown after a week for raising
About 150mm3The tumour of size.Mouse is randomly divided into 6 groups (every group 5): (1) blank control group is physiological saline PBS；(2)
PB (example 3)+NIR, 0.1mg/mLPB；(3)PB@gellan hydrogel+NIR；(4) CA4,6mg/mL；(5)CA4@
gellan hydrogel；(6) CA4+PB@gellan hydrogel (example 3)+NIR.Respectively by the sample of different experiments group into
Row mouse intratumor injection, the intratumor injection sample volume of every mouse are 200uL.Inject about 2h after, respectively to group (2), (3) and
(6) every mouse tumor position applies 808nm laser irradiation 3min, optical power density 1W/cm2.Every other day record is swollen
Knurl product and mouse weight, after treatment 22 days, after mouse is put to death in etherization, tumor tissues are collected in dissection.
Nanometer composite hydrogel (CA4+PB@gellan hydrogel) is made in heating and temperature-fall period performance in the present invention
The different rheological equationms of state, temperature lowering curve show that the sol-gel transition temperature of Nanometer composite hydrogel is about 52 DEG C, and it is bent to heat up
There is not Gel-sol transition temperature in line Nanometer composite hydrogel, illustrates the heat stagnation (Fig. 1) of Nanometer composite hydrogel.
Nanometer composite hydrogel, which is made, in the present invention has good syringeability and self- recoverage property.Rheometer characterizes miscellaneous
Change the shear shinning property of gel, with the raising of shear rate, viscosity is gradually reduced, and has invertibity (Fig. 2).Hydridization
The storage modulus of gel can be gradually reduced with the increase of strain, and when strain is approximately more than 6%, G ' < G " shows as fluidity
Matter (Fig. 3).Nanometer composite hydrogel is under 300% effects of strain, storage modulu G ' sharp fall (G ' < G "), illustrates solidifying
Glue is destroyed, and when strain is 1%, gelation immediately occurs again in 10s for system, and modulus is restored close to initial level, and
This process can be recycled repeatedly, illustrate that hybrid gel has extraordinary self-healing property (Fig. 4).
The maximum absorbing wavelength of Nanometer composite hydrogel is made near 720nm (Fig. 5) in the present invention.It is closely red in 808nm
Under the stimulation of outer light, Nanometer composite hydrogel of the invention has very excellent photo-thermal property.The variation of temperature and near-infrared
The irradiation time of light is directly proportional to power (Fig. 6).In 1.0W/cm2Power illumination 5min, PB mass concentration in 0.1mg/mL,
Temperature can rise 50 DEG C.Although Nanometer composite hydrogel of the invention can generate thermal effect under the irradiation of 808nm near infrared light
It answers, but illumination influences less the rate of release of vascular disrupting agents, hydrogel does not show burst release after near infrared light photograph, still
Have the characteristics that slow release drug (Fig. 7).
By establishing mouse subcutaneous tumor, gross tumor volume is more than 150mm3When, after 200 μ L hydrogels are subcutaneously injected, and give
Give near infrared light (808nm, a 1.0W/cm2, 3min).Research is found and single photo-thermal therapy or vascular disrupting agents
Treatment control group compares, and experimental group (CA4+PB@gellan hydrogel) has optimal antitumor synergy.Treatment 22
Discovery is dissected after it, 5 mouse gross tumor volume after treating all contracts significantly in experimental group (CA4+PB@gellan hydrogel)
It is small, wherein 2 mouse tumor tissues completely disappear, show that photo-thermal therapy can press down completely with vascular disrupting agents combination therapy means
System even melts the tumour (Fig. 8) of mouse.
Treat the volume change of tumour in latter 22 days as shown in figure 9, tumour is substantially completely cut off.Compared to control group
Speech, PB+gellan have preferable oncotherapy effect compared to individual PB, and similarly, CA4+gellan is compared to individual
CA4 has better treatment of cancer effect, but the phase all shows apparent growth trend to the tumour of four groups of mouse after the treatment, makes
There is better antitumous effect with the experimental group that composite hydrogel is handled.
Claims (10)
1. a kind of composite hydrogel for loading vascular disrupting agents and near infrared light thermal response nanoparticle altogether, which is characterized in that packet
Hydrogel substrate material is included, and the vascular disrupting agents and near infrared light thermal response nanoparticle that are supported in hydrogel substrate material
Son.
2. composite hydrogel according to claim 1, which is characterized in that the near infrared light thermal response nanoparticle is to be situated between
At least one of hole prussian blue nano particle, platinum and metal chalcogenide compound；It is further preferably mesoporous Prussian blue to receive
Rice corpuscles.
3. composite hydrogel according to claim 2, which is characterized in that the grain of the near infrared light thermal response nanoparticle
Diameter is 20~200nm.
4. composite hydrogel according to claim 1, which is characterized in that the vascular disrupting agents are health cloth sting A4, Kang Bu
At least one of sting A4 water-soluble phosphate pro-drug CA4P, DMXAA and TZT-1027；Preferably health cloth sting A4.
5. composite hydrogel according to claim 1, which is characterized in that hydrogel substrate material is in gellan gum or agar
At least one.
6. composite hydrogel according to claim 5, which is characterized in that the gellan gum is low-acyl gellan gum.
7. any one composite hydrogel according to claim 1~6, which is characterized in that in the Nanometer composite hydrogel,
Hydrogel substrate material mass percent concentration is 0.5%~5%, and the mass concentration of near infrared light thermal response nanoparticle is
0.01~1.0mg/mL, vascular disrupting agents concentration is in 1.0~10.0mg/mL.
8. a kind of preparation method of any one of claim 1~7 composite hydrogel, which is characterized in that by vascular disrupting agents,
Near infrared light thermal response nanoparticle and the dissolution of hydrogel matrix material and water mixing, are made the composite hydrogel；
Preferably, hydrogel matrix material is added in the dispersion liquid for being dispersed near infrared light thermal response nanoparticle and heats molten
Xie Hou, be cooled to not will lead to drug inactivation temperature range be added vascular disrupting agents drug, be cooled to room temperature to get.
9. compound water congealing made from preparation method described in composite hydrogel described in a kind of claim 1~7 or claim 8
The application of glue, which is characterized in that be used to prepare anti-tumor drug；
Preferably, it is used to prepare the drug of neoplasm in situ treatment；
Further preferably, it is used to prepare the drug of anti-malignant sarcomas.
10. a kind of antitumor ejection preparation, which is characterized in that include any one of claim 1~7 composite hydrogel.
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| CN112773897A (en) * | 2021-02-05 | 2021-05-11 | 中南大学 | NIR-II photoresponse hydrogel and preparation method thereof and application of NIR-II photoresponse hydrogel in preparation of anti-cancer drugs |
| CN113425671A (en) * | 2021-07-05 | 2021-09-24 | 郑州大学 | Preparation method and application of immune gel for regulating and controlling tumor microenvironment |
| CN114377128A (en) * | 2022-01-12 | 2022-04-22 | 中南大学 | Preparation and anti-tumor application of composite hydrogel co-loaded with near-infrared photothermal agent and immune drug |
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| CN109912738A (en) * | 2019-02-26 | 2019-06-21 | 陕西科技大学 | A kind of self-repair type nano-composite emulsion and preparation method thereof |
| CN109912738B (en) * | 2019-02-26 | 2020-10-13 | 陕西科技大学 | Self-repairing nano composite emulsion and preparation method thereof |
| CN112773897A (en) * | 2021-02-05 | 2021-05-11 | 中南大学 | NIR-II photoresponse hydrogel and preparation method thereof and application of NIR-II photoresponse hydrogel in preparation of anti-cancer drugs |
| CN113425671A (en) * | 2021-07-05 | 2021-09-24 | 郑州大学 | Preparation method and application of immune gel for regulating and controlling tumor microenvironment |
| CN114377128A (en) * | 2022-01-12 | 2022-04-22 | 中南大学 | Preparation and anti-tumor application of composite hydrogel co-loaded with near-infrared photothermal agent and immune drug |
| CN114377128B (en) * | 2022-01-12 | 2023-01-06 | 中南大学 | Preparation and anti-tumor application of composite hydrogel co-loaded with near-infrared photothermal agent and immune drug |
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